N-pyridoxyl-amines



Dorothea Heyl Hellman, Railway, Stanton A. Harris, Westfield, and Karl Folkers, Plainfield, N. J., assignors to Merck & (30., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. pplication- August 10, 1950, Serial No. 178,764

6 Claims. (Cl. 260-496) This invention is concerned generally with novel derivatives of pyridoxal. More particularly it relates to N-pyridoxyl substituted amines, and to the preparation of these compounds by condensing pyridoxal with pritjnarydamines and hydrogenating the'S'chiif base thus prouce This application is a continuation-in-part of application Serial No. 792,618, filed December 18, 1947, now Patent No. 2,540,946.

These novel N-pyridoxylramines, and in particular those derived from naturally-occurring amino acids, act as depressors, that is, as agents which are useful in lowering blood pressure. These compounds may be coupled with aromatic diazonium compounds to yield colored products which are useful as dyes. These compounds are also of value as growth-promoting agents.

These N-pyridoxyl-amines' may be chemically representedas follows:

an -.Nn-n

wherein R is an alkyl, aryl, aralkyl or heterocyclicradical. Examples of these N-pyridoxyl-amines are: N-pyridoxyl-aniline, N-pyridoxyl-benzylamine, N-pyridoxylpyridoxamine, N-pyridoXyl-methylamine, N-pyridoxylethylamine, N-pyridoxyl-phenylpropylamine, and the like. The preferred N-pyridoxyl-amines' are the N-pyridoxylhydroxy-alkylamines, such as N-pyridoxyl-fi-hydroxyethylamine, N-pyridoxyl-fi-hydroxy-propylamine, N-pyr- 'idoxyl-polyhydroxy-aralkylamines such as N-pyridoxyl- 3,4-dihydroxy-B-phenylethylamineand N-pyridoxylpolyhydroxyaryl hydroxyalkylamines suchas N-pyridoxylarterenol, that is N-pyridoxyl- 18 -hydroxy-fl-(3,4-dihydroxy-phenyl)-ethylamine. We particularly prefer the N-pyridoxyl-amines in which the parent amine, (RNHz) is derived from a naturally-occurring amino acid, as for example N-pyridoxyl-tyramine, N-pyridoxyl-trypt'amine, N pyridoxyl-fi-phenyl-ethylamine, N pyridoxyl-hista'mine, and the like.

We have discovered that these N-pyridoxyl-amin'e compounds can be prepared by reacting pyridoxal with the appropriate amine to form a Schiils base which isthen hydrogenated to produce thedesired N-pyridoXyl-amine. The general method of preparing secondary amines by reacting aldehydes with primary amines and reducing the 'Schiifs bases thus formed is, of course, a well-known text-book procedure. The possibility that such a procedure, starting with pyridoxal, would be applicable for'the preparation of the'herein disclosed N-pyridoxyl-amines ,was, however, extremely remote. Pyridoxal is not an ordinary aldehydei but is a complexpolyfunctional heterocycle possessing several reactive groupings. Previously .itfhad been found that pyridoxal, in solution, instead of existing in the fonn whereinthe substituent in the 4-position is an aldehyde grouping, ordinarily'exists iritheform of a hemiacetal wherein the carbon atom attached to the 4-position of the pyridine nucleus is bridged to the methylene grouping attached to the 5-position by means of an' ether linkage. SincePyridoxal', in solution, contains no free aldehyde grouping; it iwould have been expected that pyridoxal would not react with primary amines to'form'Schifts bases. .j. .Moreover, when weattjernptedt'o prepare Schiifs bases United States Patent 0 "cc 2,695,297 Patented Nov. 23, 1954 by reacting pyridoxal with certain primary amines, such as histamine and the dihydroxy-phenylethylamines, the products thus obtained were not the corresponding Schififs bases but were, instead, polycyclic compounds. For example, when pyridoxal and histamine are condensed in aqueous alcohol, the product obtained is not a Schiifs base but is a white material which melts at approximately 252-253 C. dec., and which does not absorb hydrogen under the conditions describedhereinabove for preparing N-pyridoxyl-amines. SimilarlY,. When pyridoxal is reacted with a dihydroxy-phenylethylamine and the reaction is carried out in a single soluble phase, as for example in alcohol solution, an intra molecular ring formation occurs and the product obtained is not a Schitis base but is, instead, a quinoline derivative.

We have now discovered, however, an improved procedure whereby this intramolecular ring formation can be avoided and whereby pyridoxal can be reacted with primary amines (including histamine'and the dihydroxyphenylethylamines) followed by hydrogenation to produce the corresponding N-pyridoXyl-amines. This is accomplished by conducting the reaction in a medium comprising a substantially anhydrous lower aliphatic alcohol such as ethanol, methanol, and the like, under which conditions the desired pyridoxal-amine Schiifs base is formed.

in some instances, the Schifis base, which is usually a yellow compound, may be conveniently recovered from the reaction mixture. For example, when pyridoxal and histamine are reacted together in substantially anhydrous alcohol solution, the yellow pyridoXal-histamine Schiffs base ,(M. P. 240-241" C.) precipitates and may be recovered by filtration. When this yellow pyridoxal-histamine compound is reacted with hydrogen, the compound (in contrast to the white pyridoxal-histamine hereinabove referred to) absorbs hydrogen to form N-pyridoXyl-histamlne.

it is ordinarily preferred, however, particularly when preparing N-pyridoxyl dihydroxyphenylethylamines, to subject the alcoholic reaction solution, substantially in the form obtained by reacting pyridoxal and primary amine in absolute alcohol, to the action of hydrogen, in the presence of a hydrogenation catalyst, such as platinum. In fact, the condensation between pyridoxal and dihydroxyphenylethylamines is best carried out in a combination of liquid and solid phases and in the presence of the hydrogen reducing agent. This is conveniently accomplished by dissolving the hydrochloride of the dihydroxyphenylethylamine in a lower aliphatic alcohol, such as methanol, adding solid pyridoxal and a hydrogenation catalyst, then adding pellets of sodium hydroxide and immediately subjecting the resulting mixture to hydrogenation. As the starting materials slowly dissolve and react, the intermediate product is hydrogenated to produce the desired N-pyridoxyl-dihydroxyphenylethylamine.

As noted hereinabove, the N-pyridoxyl-amines, prepared according to the present invention, act as depressors, which action is particularly surprising in view of the fact that the corresponding parent amines, tyramine, tryptamine and fl-phenylethylamine all act as pressors, that is, as agents which raise the blood pressure. Moreover, the intermediate Schiii base, obtained by the condensation of pyridoxal and the amine does not exhibit the depressor activity, characteristic of the hydrogenated product, the N-pyridoxyl-amine.

in addition to the above-mentioned depressor activity, these N-pyridoxyl-amines have also been found to show a high order of vitamin B6 activity. For example, N-pyridoxyl-isopropanol amine, N pyridoxyl phenylprop'ylamine, N-pyridoxyl-aniline, N-pyridoxyl-tyramine, N-pyridoxyl-isobutylamine, N-pyridoxyl-tryptamine, N-pyridoxyl-B-phenylethylamine, N-pyridoXyl-ethylamine and N-pyridoxyl-ethanolamine, when bioassayed for vitamin Ba potency by the'curative method with rats, exhibited from 75 to of the activity shown by vitaminBs itself. All other N-pyridoxyl-ainines' tested likewise exhibited significant, although somewhat lower, vitamin B6 activity. The fact that the N-pyridoxyl-amines show vitamin B6 activity is particularly unexpected in view o f the fact that it was previously considered that vitamin 3 Ba owes its physiological action to the molecule as an entity, which conclusion was based on the discovery that previously known components of very similar structure, as well as simple derivatives of vitamin B6, were found to be inactive.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

EXAMPLE 1 About 4.15 gms. of tyramine and about 5.06 gms. of pyridoxal are suspended in about 100 cc. of absolute methyl alcohol. After minutes standing, a clear yellow solution is obtained. This solution is filtered, diluted to about 150 cc. with methyl alcohol, 0.2 mg. of Adams platinum catalyst is added and the resulting mixture is shaken under hydrogen at a pressure of approximately 2-3 atmospheres for approximately /2 hour. The catalyst is removed by filtration, cooled in an ice bath, and alcoholic hydrogen chloride is added slowly until the solution is acid to Congo red. The solution is cooled for an additional period of time and the crystals which precipitate are filtered and washed with alcohol and ether to produce approximately 9.6 gms. of N-pyridoxyl-tyramine dihydrochloriclle; M. P. 238-239 C.; yield approximately 88% of theory.

EXAMPLE 2 About 3.62 gms. of B-phenyl-ethylamine and about 5.00 gms. of pyridoxal are dissolved in 150 cc. of absolute methyl alcohol and the resulting mixture stirred for approximately /2 hour, at which time the reaction is substantially complete. The bright yellow solution thus obtained is filtered and evaporated to dryness under reduced pressure. The residual material is recrystallized from ether-petroleum ether, and dried to produce approximately 6.90 gms. of pyridoxal-[3-phenyl-ethylamine;

yield approximately 86% of theory. This product is removed by filtration and the filtrate evaporated to approximately cc. Alcoholic hydrogen chloride is added, while cooling the resulting mixture by immersion in an ice bath, until the solution is acid to Congo red.

The crystals which separate from the solution are recovered and dried to produce approximately 5.18 gms. of N-pyridoxyl-fi-phenylethylamine yield approximately 85% of theory. This product is further purified by two recrystallizations from methyl alcohol-ether to produce substantially pure material;

EXAMPLE 3 About 1.00 gm. of tryptamine and about 1.04 gms. of pyridoxal are dissolved in cc. of absolute ethyl alcohol and the resulting mixture stirred for approximately 5 minutes, at which time the reaction is substantially complete. The clear yellow solution thus obtained is filtered and evaporated to dryness under reduced pressure. The residual material is recrystallized from ethyl alcohol and dried to produce approximately 1.4

gms. of pyridoxal-tryptamine; M. P. l60.5-161.0 C.; F

yield approximately 73% of theory.

125 cc. of absolute methyl alcohol containing 1.00 gm. of pyridoxal-tryptamine and about 0.1 gm. of Adams platinum catalyst is shaken under hydrogen at a pressure of approximately 23 atmospheres until the theoretical amount of hydrogen has been absorbed and the solution has become colorless. The catalyst is removed by filtration and the filtrate evaporated to about 30 cc. Alcoholic hydrogen chloride is added, while cooling the resulting mixture by immersion in an ice bath, until the pH of the solution is approximately 6.0 Ether is then added to the resulting alcoholic solution to precipitate the crude monohydrochloride, which is recrystallized from aqueous alcohol to produce 095 gm. of sub stantially pure N-pyridoxyl-tryptamine hydrochloride;

the colorless solution is dihydrochloride;

messes M. P. 2225-2210" c.; yield approximately 84% of theory.

EXAMPLE 4 About 3.31 gms. of pyridoxamine and about 3.30 gms. of pyridoxal are shaken with about 400 cc. of ethyl alcohol for approximately 5 hours at which time the reaction is substantially complete. The resulting solution is clarified by filtration and the filtrate evaporated to dryness under reduced pressure. The residual material is recrystallized from ethyl alcohol and dried to produce approximately 4.19 gms. of pyridoxal-pyridoxamine; M. P. 232233 0.; yield approximately 67% of theory.

400 cc. of ethyl alcohol containing about 2 gms. of pyridoxal-pyridoxamine was shaken with 0.15 gm. of Adams platinum catalyst under 2-3 atmospheres of hydrogen. After removal of the catalyst by filtering, the solution was concentrated to dryness. The residue was dissolved in ethyl alcohol, cooled in an ice bath, and made acid to Congo red by the dropwise addition of alcoholic hydrogen chloride. The crystals of N-pyridoxyl-pyridoxamine dihydrochloride, after filtering and washing with alcohol, were obtained in a yield of 0.74 g.; yield approximately 30% of theory. After two recrystallizations from aqueous alcohol, the melting point was 222-223" C. dec. Analysis Calcd for C1sH23NaO4Cl2: C, 48.98; H, 5.01; N, 10.71. Found: C, 49.42; H, 6.23; N, 10.63.

7 EXAMPLE 5 About 0.68 gm. of tyramine and about 0.83 gm. of pyridoxal are dissolved in 35 cc. of absolute methyl alcohol and the resulting mixture is stirred for approximately 5 minutes at which time the reaction is substantially complete. The resulting solution is filtered and evaporated to dryness under reduced pressure. The residual material is recrystallized 4 times, first from alcohol, and then from alcohol-ether-petroleum ether to produce approximately 1.28 gms. of pyridoxal-tyramine; M. P. 168.0168.5 C.; yield approximately of theory.

About 125 cc. of absolute methyl alcohol containing about 0.59 gm. of pyridoxal-tyramine and about 0.1 gm. of Adams platinum catalyst, is shaken under hydrogen at pressure of approximately 2-3 atmospheres until the theoretical amount of hydrogen is adsorbed and the solution has become colorless. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residual material is dissolved in ethyl alcohol and alcoholic hydrogen chloride is added to the resulting solution, with cooling, until the solution is acid to Congo Red. The crystals which separate from the solution are re covered and purified by recrystallization from wateralcohol-ether to produce approximately 0.5 gm. of N- pyridoxyl-tyramine dihydrochloride; M. P. 234-235 (1.; yield approximately 66% of theory.

EXAMPLE 6 About 3 drops of aniline and about 0.1 gm. of pyridoxal are dissolved in 10 cc. of absolute ethyl alcohol, and the resulting mixture'is heated at the boiling point for approximately 5 minutes, at-which time the reaction is substantially complete. The resulting solution is filtered and evaporated to dryness under reduced pressure to produce substantially pure pyridoxal-aniline; M. P. l78.5179.0 C.

1.5 gm. of pyridoxal-aniline, prepared as described above, is dissolved in 35 cc. of methyl alcohol, and the solution is hydrogenated over 0.1 g. of Adams platinum catalyst. When the theoretical amount of hydrogen has been absorbed the catalyst is separated by filtering the hydrogenation mixture, and the filtrate is chilled and made acid to about pH 6 with alcoholic hydrogen chloride. Ether is added to the resulting solution whereupon a crystalline precipitate forms, which is recovered by filtration, washed with alcohol-ether and then with ether, and dried to produce 1.49 g. of N-pyridoxyl-aniline hydrochloride; M. P. 230-232" C.; yield 87% of theory. AnalysisCalcd for C, 59.89; N, 6.11; N,9.98. Found: C, 59.95; H, 6.05; N, 10.40

EXAMPLE 7 About 1.84 gm. of histamine dihydrochloride are dissolved in about 5 cc. of water and about 1.68 gm. of potassium hydroxide in about 5 cc. of water is added to this solution. About cc. of ethyl alcoholis added to this solution followed by about 1.67 gm. of pyridoxal. The initial bright yellow color gradually yield the resulting solution to fades and a thick white precipitate appears. The resultingmixture is allowed to stand for approxlmately /2 hour and then cooled in ice. The white crystalline precipitate is recovered by filtration and washed'thoroughly with water followed by alcohol and then ether. The product is dried to produce approximately 0.76 gm. of pyridoxal-histamine (saturated isomer); M. P. 252-253 C. dec.: yield approximately 29% of theory.

'A sample of pyridoxal histamine, prepared as described above, and dried at approximately 100 C. (1 mm. pressure) for approximately 4 hours, analyzed as follows: Analysis-Calcd for C13H16N4O2: per cent C, 59.98; per cent H, 6.20; per cent N, 21.53. Found: per cent C, 60.14; per cent H, 6.10; per cent N, 21.39.

EXAMPLE 8 About 1.07 gm. of benzylamine and about 1.67 gm. of pyridoxal are dissolved in 40 cc. of absolute ethyl alcohol and the resulting mixture stirred for approximately 5 minutes, at which time the reaction is substantially complete. The reaction solution is filtered and evaporated to dryness under reduced pressure. The residual material is recrystallized lrom alcohol-ether-petroleum ether to produce approximately 0.9 gm. of pyridoxal-benzylamine; M. P. '113.5114.5 C; yield approximately 35% of theory.

5 cc. of absolute methyl alcohol containing 0.40 gm. of pyridoxal-benzylamine and about 0.1 gm. of Adams platinum catalyst is shaken under hydrogen at a pressure of approximately 2-3 atmospheres until the theoretical quantity of hydrogen has been absorbed and the solution has become colorless. The catalyst is removed by filtrationand the filtrate evaporated to dryness. The residual material is dissolved in ethyl alcohol, and alcoholic hydrogen chloride is added to the resulting solution, with cooling, until the solution is acid to Congo red. Ether is then added to the alcoholic solution to precipitate the crude dihydrochloride, and this product is recrystallized 3 times from alcoholether solution (a few drops of alcoholic hydrogen chloride are added during the last recrystallization) to prod ce'approximately 0.28 gm. of N-pyridoxyl-benzylamine dihydrochloride; M. P. 219-220 C.; yield approximately 54% of theory.

EXAMPLE 9 About 2.00 gms. of isobutylamine and about 4.56 gms. of pyridoxal are dissolved in 30 cc. of absolute ethyl alcohol and the resulting mixture stirred for approximately 1 hour, at which time the reaction is substantially complete. The resulting solution is filtered and evaporated to dryness under reduced pressure. The residual material is dissolved in ether-petroleurn-ether solvent by heating and the solution iscooled whereupon unreacted pyridoxal crystallizes at once and is removed by filtration. The filtrate is allowed to stand whereupon pyridoxal isobutylamine crystallizes and is recovered by filtration and dried; M. P. 67-68 C.; approximately, of theory. Analysis Calcd for C12H18N202I per cent C, 64.84; per cent H, 8.16; per cent N, 12.61. Found: per cent C, 64.89; per cent H, 8.05; per cent N, 12.77.

125 cc. of absolute methyl alcohol containing about 2.66 gms. of pyridoxal isobutylamine and about 0.1 gm. of Adams platinum catalyst is shaken under hydrogen at a pressure of approximately 2-3 atmospheres until the' theoretical amount of hydrogen has been absorbed and the solution has become colorless. The catalyst is removed by filtration and the filtrate is evaporated'to about 30 cc. volume. Alcoholic hydrogen chloride is added with cooling until the pH of the solution is approximately 6.0. Ether is then added to a precipitate- N-pyridoxyl-isobutlyamine monohydrochloride, which is recovered by filtration and dried; M. P. 204-205 C. dec.; yield approximately. of theory. Analysis--Calcd for C12H2 N2O2Cl: per cent C, 55.27; per cent H, 8.12; per cent N, 10.75. Found: per centC, 55.57; per cent H, 7.90; per cent N, 10.67.

EXAMPLE 10 A suspension of about 5.0 gms. of histamine dihydrochloride and 5.0 gms. of sodium bicarbonate in 150 cc. 0? absolute ethyl alcohol. is heated at theTboiI-ing point for. approximately 3.5 .Ininutes. "The. insohible. inorganic' material is recovered by filtration and the al.- coholic solution treated with approximately 4.5 gms. of pyridoxal; The solution is stirred for approximately 1 hour and the resulting thick, bright yellow precipitate is recovered by filtration. Additional crystals are obtained by cooling the filtrate to produce a total yield of crude condensation product equal to approximately 2.93 gms. This material is recrystallized from alcohol to produce substantially pure pyridoxal-histamine (unsiaturated Schifl? base modification); M. P. 240-241 C.

1.0 gm. of pyridoxal histamine, prepared as described above, is dissolved in about 300 cc. of absolute methyl alcohol, 0.1 gm. of Adams platinum catalyst is added and the mixture shaken under hydrogen at a pressure of approximately 2-3 atmospheres until the-theoretical amount of hydrogen has been absorbed. The catalyst is removed by filtration and the filtrate is evaporated to small volume and excess alcoholic hydrogen chloride added to the concentrated solution. The crude crystals which precipitate. are recovered by filtration and dried to produce approximately 1.3 gm. of crude N-pyridoxyl-histamine dihydrochloride. This product is purified by three recrystallizations from ethyl alcoholwater to produce substantially pure N-pyridoxyl-histamine dihydrochloride; M. P. 2 36237 C. dec.

A sample of N-pyridoxyl-histamine dihydrochloride prepared as described above, and dried at about C. (1 pressure) for approximately 1 /2 hours, analyzed as follows: Analysis.-Calcd for C13H20N4O2Cl2: per cent C, 46.57;per cent H, 6.01; per cent N, 16.71. Found: Per cent C, 46.84; per cent H, 6.10; per cent N', 16.96.

EXAMPLE 1 l Methylamine is generated by the dropwise addition of a saturated solution of methylamine hydrochloride into concentrated aqueous potassium hydroxide. The lead out tube is connected to a potassium hydroxide drying tube, and the dried methylamine is bubbled into 100 cc. of methyl alcoholcontaining 8.0 g. of pyridoxal in suspension. When all the pyridoxal has reacted, the bright yellow solution is filtered and chilled. The pyridoxalmethylamine which crystallizes (3.2 g., M. P. -151 C.) is collected on a filter and subsequently dried at 60 C. (1 mm.) Analysis-Calcd for C9H12N2Oz: C, 59.98; N, 6.72; N, 15.55. Found: C, 60.22; H, 6.87; N, 15.34.

The filtrate from the preparation of pyridoxal-methylamine is hydrogenated in the presence of 0.2 g. of Adams platinum catalyst. After collection of thecatalyst on a filter, the filtrate is chilled, and alcoholic hydrogen chloride is added to a pH of about 6. N-pyridoxylmethylamine hydrochloride (4.28 g.; yield 66% of theory), precipitated with ether, is washed well with a mixture of alcohol and ether, followed by ether alone. It is dried at 100 C. (1 mm.) and melts at 208-209 C. Analysis.Calcd for C9H15N2O2Cl: C, 49.43; H, 6.91; N, 12.81. Found: C, 49.70; H, 6.87; N, 12.86.

EXAMPLE 12 A suspension of 8.0 g. of pyridoxal in 50 cc. of methyl alcohol containing 3.8. g. of ethylamine is stirred until all of the pyridoxal has reacted-about ten minutes. The solution is filtered through fine-grained sintered glass, and the excess of ethylamine is removed from the solution by a stream of nitrogen. One third of the reaction mixture is concentrated to dryness under diminished pressure, a tepid water bath being used for heating. The residue, crystallized from ether, yields 2.16 g. (yield 88% of theory) of pyridoxal-ethylamine; M; P. IDS-109 C. Analysis.Calcd for C1oH14N2O2: C, 61.83; H, 7.26; N, 14.43. Found: C, 62.07; H, 7.23; N, 14.69. t

A solution of 6.20 g. of pyridoxal-ethylamine is reacted with hydrogen over Adams platinum catalyst. After removal of the catalyst by filtering, the filtrate is chilled and acidified to about pH 6 With alcoholic hydrogen chloride. Crystals of N-pyridoxylethylamine hydrochloride, M. P. 184-186 C, precipitate on cooling. Asecond crop is obtained when ether is added tothe filtrate, raising the.yie1dto.6.96 g. (yield 92% of theory). Analysis- Calcd for CmHwNzOzCl: C, 51.61; H, 7.38; N, 12.04. Found: C, 51.91; H, 7.16; N, 12.22.

EXAMPLE 13 for about minutes. The practically clear solution is filtered and chilled. N-pyridoxal-y-phenylpropylamine is obtained in a yield of 1.57 g. (the rest of the material remains in solution). After recrystallization from etherpetroleum ether this product melts at 8789 C. 'Analysis.Calcd for C1'1H20N202: C, 71.80; H, 7.09; N, 9.85. Found: C, 71.62; H, 7.07; N, 10.12.

The filtrate of N-pyridoxal-v-phenylpropylamine (containing theoretically 6.93 g.) is hydrogenated over Adams platinum catalyst. After the catalyst has been removed by filtering, the filtrate is chilled and made acid to about pH6 with alcoholic hydrogen chloride. Addition of ether precipitates crystals of N-pyridoxyl-' -phenylpropylamine hydrochloride in a yield of 5.94 g. (yield 76% of theory), M. P. 180-181" C. Analysis.Calcd for CnHzsNzOzCl: C, 63.25; H, 7.18; N, 8.68. Found: C, 63.24; H, 6.99; N, 8.68.

EXAMPLE 14 To a suspension of 1.00 g. of pyridoxal in 20 cc. of methyl alcohol, 0.37 g. of hydroxyethylamine is added. Since after an hour of stirring all the pyridoxal has not reacted, a little more hydroxyethylamine and methyl alcohol is added. After an additional five hours stirring, .unreacted pyridoxal is removed by filtering. The filtrate is concentrated to dryness under reduced pressure and the residue is crystallized from methyl alcohol-ether. N-pyridoxal-fl-hydroxyethylarnine is obtained in a yield of 1.08 g. (yield 87% of theory). After recrystallization from methyl alcohol the material melts at 148149 C. Analysis.Calcd for CroHmNzOs: C, 57.13; H, 6.71; N, 13.32. Found: C, 57.41; H, 6.47; N, 13.03.

A solution of 1.83 g. of hydroxyethylamine in 300 cc. of absolute methyl alcohol is treated with 5.01 g. of .pyridoxal. Gradually a clear yellow solution is formed, which requires twenty-four minutes for hydrogenation over 0.2 g. of Adams platinum catalyst. The solution is filtered as quickly as possible, but a small amount of white crystalline material remains with the catalyst on the filter. After the filtrate has been cooled in an ice bath, the crystals of N-pyridoxyl-hydroxyethylamine (M. P. 174l75 C., 4.9 g.) are collected on a filter. Another 1.2 g. of material recovered from the filtrate and catalyst brings the total yield to 95% of theory. Analysis.Calcd for Ciel-116N203: C, 56.58; H, 7.60; N, 13.20. Found: C, 56.64; H, 7.66; N, 13.42.

EXAMPLE 15 To a solution of 3.15 g. of fihydroxypropylamine in '50 cc. of methyl alcohol, 7.00 g. of pyridoxal is added with stirring. After twenty minutes the reaction mixture is filtered through sintered glass. One third of the filtrate is concentrated to dryness under reduced pressure. The resulting residue is dissolved in alcohol. Addition of ether and petroleum ether brings out crystals of N- pyridoxal-B-hydroxypropylamine in a yield of 2.21 g. (yield 70% .of theory); M. P. 1l2l14 C. Analysis.- Calcd for C11H16N203: C, 58.91; H, 7.19; N, 12.49. Found: C, 58.76; H, 6.91; N, 12.61.

The remaining two thirds of the solution of N-pyridoxal-fl-hydroxypropylamine is hydrogenated in the presence of Adams platinum catalyst. The product crystallizes at once and is collected on a filter together with the catalyst. The N-pyridoxyl-fi-hydroxypropylamine is extracted with cold dilute hydrochloric acid, and reprecipitated with sodium bicarbonate. After collection on a filter, the material is washed with water, methyl alcohol, and ether, and then dried. The yield of N-pyridoxyLB- hydroxypropylamine thus obtained is 6.63 g. (yield 67% of theory); M. P. 194-196 C. Analysis.Calcd for C11H18N2031 C, 58.39; H, 8.02; N, 12.38. Found: C, 58.21; H, 7.78; N, 12.46.

EXAMPLE 16 For purification, this material is dissolved in 20 cc. of ice water, and is then treated with an excess of sodium bicarbonate. The resulting sticky oil is separated and a solution of it in alcohol is filtered through a sintered glass funnel. The clear filtrate, cooled in ice, is made acid with alcoholic hydrogen chloride. The pure crystals of N pyridoxyl-3,4-dihydroxy-fi-phenylethylamine dihydrochloride melt at 241242 C. dec. The analytical sample is dried at C. (1 mm.). Analysis.Calcd for C1eH22N204Cl2: C, 50.93; H, 5.88; N, 7.43. Found: C, 51.09; H, 5.62; N, 7.69.

EXAMPLE 17 If instead of immediately hydrogenating the product obtained by reacting pyridoxal with 3,4-dihydroxy-flphenylethylamine (as described in Example 16), the reaction solution is allowed to stand, the product obtained is 1 (2 methyl 3 hydroxy-S-hydroxymethyl-4-pyridyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquincline, having the following formula:

H0 CHzOB'.

CH3 N For example, a solution of 0.93 g. of 3,4-dihydroxy-pphenylethylamine hydrobromide and 0.21 g. of potassium hydroxide in about 25 cc. of methyl alcohol is treated with 0.63 g. of pyridoxal. When most of the pyridoxal has disappeared, the solution is filtered. Crystals of the free base of the condensation product appear almost at once in the filtrate. After brief cooling, the crystals are collected on a filter and are washed with methyl alcohol. The crystals, suspended in ice cold ethyl alcohol, are converted to the hydrochloride by addition of alcoholic hydrogen chloride. Addition of ether fails to bring down anything but a small amorphous precipitate. The clear solution is decanted and concentrated to dryness under reduced pressure. The residue, dissolved in ice water, is neutralized with sodium bicarbonate. The thick precipitate which forms, is collected on a filter and washed thoroughly with water, alcohol and ether, and dried to produce 0.50 g. of l-(2-rncthyl-3hydroxy-S-hydroxymethyl- 4-pyridyl)-6,7-dihydroxy-1,2,3,4 tetrahydroisoquinoline; M. P. 242-244 C. dec.; yield 44% of theory. The analytical sample is dried at C. (1 mm.). Analysis. Calcd for C16H18N2042 C, 63.56; H, 6.00; N, 9.27. Found: C, 63.16; H, 5.95; N, 9.09.

N-pyridoxylarterenol dihydrochloride 0.15 g. of sodium hydroxide is added to a suspension of 0.64 g. of pyridoxal and 0.15 g. of Adams platinum catalyst in 50 cc. of methyl alcohol containing 0.79 g. of arterenol hydrochloride, [,8 hydroxy B (3,4-dihydroxyphenyl)-ethylamine hydrochloride]. The mixture is immediately shaken with hydrogen. After fifteen minutes, the absorption of hydrogen ceases, and the solution appears colorless. A carbon dioxide atmosphere is maintained over the solution until it has been acidified with hydrogen chloride in methyl alcohol. Addition of ether causes crystallization of 0.93 g. (62%) of N-pyridoxylarterenol dihydrochloride. This material is purified by neutralization with aqueous sodium bicarbonate solution, solution of the free amine in ethyl alcohol, and subsequent reacidification with alcoholic hydrogen chloride. The purified N-pyridoxylarterenol hydrochloride [N-pyridoxyl-fl-hydroxy-B-G,4-dihydroxyphenyl)-ethylamine dihydrochloride] melts at 177-178 C., dec. The analytical sample dried at 100 C. (1 mm.) shows the following analysis: Analysis.-Calcd for CmHzzNzOsClz: C, 48.86; H, 5.64; N, 7.13. Found: C, 49.10, H, 5.83; N, 7.08.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. N-pyridoxyl-tyramine dihydrochloride.

2. N-pyridoxyl-B-phenyl-ethylamine dihydrochloride.

3. N-pyridoxyl-tryptamine hydrochloride.

4. N-pyridoxyl-histamine dihydrochloride.

5. N-pyridoxyl B hydroxy-fl-(3,4-dihydroxy-phenyl)- ethylamine dihydrochloride.

6. Compounds selected from the group which consists of the following N-pyridoxyl-amines: N-pyridoxyl-tyramine, N-pyridoxyl 8 phenyl ethylamine, N-pyridoXyltryptamine, N-pyridoxyl-pyridoxamine, N-pyridoxyl-benzylamine, N-pyridoxyl-isobutylamine, N-pyrido'xyl-histamine, N-pyridoxyl-aniline, N-pyridoxyl-methylamine, N- pyridoxyl-ethylamine, N-pyridoxyl-'y-phenylpropylamine,

N-pyridoxyl 8 hydroxyethylamine, N-pyridoxyl p hydroxy-propylamine, Npyridoxyl-3,4-dihydroxy-[3-phenylethylamine, N-pyridoxyl B hydroxy )3 (3,4-dihydroxyphenyl)ethylamine; and hydrochloric acid salts of said N-pyridoxyl-amines.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date Hoffman et al. Feb. 6, 1951 OTHER REFERENCES 

1. N-PYRIDOXYL-TYRAMINE DIHYDROCHLORIDE. 